3-benzylaminopiperidines as tachykinin receptor antagonists

ABSTRACT

The present invention relates to certain 3-benzylaminopiperidines which are tachykinin receptor antagonists and are useful in the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia.

This application is a 371 of PC7/GB96/02998 filed Dec. 6, 1996.

This invention relates to a class of azacyclic compounds, which areuseful as tachykinin antagonists. More particularly, the compounds ofthe invention comprise an azacyclic ring system substituted by anaralkylamino moiety.

The tachykinins are a group of naturally occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in peripheral nervous and circulatory systems.

The tachykinins are distinguished by a conserved carboxyl-terminalsequence:

Phe-X-Gly-Leu-Met-NH₂

At present, there are three known mammalian tachykinins referred to assubstance P, neurokinin A (NKA, substance K, neuromedin L) andneurokinin B (NKB, neuromedin K) (for review see J. E. Maggio, Peptides(1985) 6(suppl. 3), 237-242). The current nomenclature designates thethree tachykinin receptors mediating the biological actions of substanceP, NKA and NKB as the NK₁, NK₂ and NK₃ receptors, respectively.

Evidence for the usefulness of tachykinin receptor antagonists in pain,headache, especially migraine, Alzheimer's disease, multiple sclerosis,attenuation of morphine withdrawal, cardiovascular changes, oedema, suchas oedema caused by thermal injury, chronic inflammatory diseases suchas rheumatoid arthritis, asthmalbronchial hyperreactivity and otherrespiratory diseases including allergic rhinitis, inflammatory diseasesof the gut including ulcerative colitis and Crohn's disease. ocularinjury and ocular inflammatory diseases, proliferativevitreoretinopathy, irritable bowel syndrome and disorders of bladderfunction including cystitis and bladder detruser hyper-reflexia isreviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists",C. A. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J. Auton.Pharmacol. (1993) 13, 23-93.

For instance, substance P is believed inter alia to be involved in theneurotransmission of pain sensations [Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (1987) 8, 506-510], specifically in thetransmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem,(1982) 25, 1009) and in arthritis [Levine et al Science (1984) 226,547-549]. Tachykinins have also been implicated in gastrointestinal (GI)disorders and diseases of the GI tract such as inflammatory boweldisease [Mantyh et al Neuroscience (1988) 25(3), 817-37 and D. Regoli in"Trends in Cluster Headache" Ed. Sicuteri et al Elsevier ScientificPublishers, Amsterdam (1987) page 85)] and emesis [F. D. Tattersall etal, Eur. J. Pharmacol., (1993) 250, R5-R6]. It is also hypothesised thatthere is a neurogenic mechanism for arthritis in which substance P mayplay a role [Kidd et al "A Neurogenic Mechanism for SymmetricalArthritis" in The Lancet, Nov. 11, 1989 and Gronblad et al,"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12), 1807-10]. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and osteoarthritis, and fibrositis[O'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8]. Otherdisease areas where tachykinin antagonists are believed to be useful areallergic conditions [Hamelet et al, Can. J. Pharmacol. Physiol. (1988)66, 1361-7], immunoregulation [Lotz et al, Science (1988) 241, 1218-21and Kimball et al, J. Immunol. (1988) 141(10), 3564-9] vasodilation,bronchospasm, reflex or neuronal control of the viscera [Mantyh et al,PNAS (1988) 85, 3235-9] and, possibly by arresting or slowingβ-amyloid-mediated neurodegenerative changes [Yankner et al, Science(1990) 250, 279-82] in senile dementia of the Alzheimer type,Alzheimer's disease and Down's Syndrome.

Tachykinin antagonists may also be useful in the treatment of small cellcarcinomas, in particular small cell lung cancer (SCLC) [Langdon et al,Cancer Research (1992) 52, 4554-7].

Substance P may also play a role in demyelinating diseases such asmultiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod etal, poster C.I.N.P. XVIIIth Congress, Jun. 28th-Jul. 2nd 1992], and indisorders of bladder function such as bladder detrusor hyper-reflexia(Lancet, May 16th 1992, 1239).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosus (Europeanpatent specification no. 0 436 334), ophthalmic disease such asconjuctivitis, vernal conjunctivitis, and the like, and cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis (European patent specification no. 0 394989).

International Patent Specification no. WO 95/08549 discloses piperidinederivatives as tachykinin receptor antagonists of the general formula##STR1## wherein R^(1b) is C₁₋₄ alkoxy; R^(2b) is optionally substitutedtetrazolyl;

R^(3b) is hydrogen or halogen;

R^(4b) and R^(5b) hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or CF₃ ;and

x is zero or 1.

The present invention provides a further class of non-peptides which areantagonists of tachykinins, especially of substance P.

Thus, the present invention provides compounds of formula (I), andpharmaceutically acceptable salts and prodrugs thereof: ##STR2## whereinR¹ represents a 5- or 6-membered aromatic heterocyclic group containing1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulphur,which is optionally substituted by one or two substituents, selectedfrom C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, SR^(x),SOR^(x), SO₂ R^(x), phenyl, NR^(a) R^(b), NR^(a) COR^(x), CH₂ COCF₃ andCF₃, where R^(a) and R^(b) are independently hydrogen or C₁₋₄ alkyl andR^(x) is C₁₋₄ alkyl;

R² represents halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, OCF₃, NO₂, CN,SR^(a), SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl,C₂₋₆ alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, where R^(a) andR^(b) each independently represent hydrogen or C₁₋₄ alkyl;

R³ represents hydrogen or C₁₋₆ alkyl;

R⁴ represents hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, CF₃,NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆alkenyl, C₂₋₆ alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, whereR^(a) and R^(b) each independently represent hydrogen or C₁₋₄ alkyl;

R⁵ represents hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted byC₁₋₄ alkoxy or CF₃ ;

R^(6a) represents hydrogen or C₁₋₆ alkyl;

R^(6b) represents C₁₋₆ alkyl optionally substituted by a hydroxy groupor the group --CO₂ R^(c), where R^(c) represents C₁₋₆ alkyl;

R⁹ represents halogen, C₁₋₆ alkyl, oxo, CO₂ R^(a) or CONR^(a) R^(b) ;

m is zero or 1;

n is 1 or 2;

p is zero, 1 or 2; and

q is zero, 1 or 2.

As used herein, the definition of each expression, when it occurs morethan once in any structure, is intended to be independent of itsdefinition elsewhere in the same structure.

As used herein, the term "alkyl" or "alkoxy" as a group or part of agroup means that the group is straight or branched. Examples of suitablealkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyland t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

The cycloalkyl groups referred to herein may represent, for example,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitablecycloalkylalkyl group may be, for example, cyclopropylmethyl.

As used herein, the terms "alkenyl" and "alkynyl" as a group or part ofa group means that the group is straight or branched. Examples ofsuitable alkenyl groups include vinyl and allyl. A suitable alkynylgroup is propargyl.

When used herein the term halogen means fluorine, chlorine, bromine andiodine. The most apt halogens are fluorine and chlorine of whichfluorine is preferred.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

The compounds according to the invention may exist both as enantiomersand as diastereomers. In particular, the relative orientation of the 2-and 3- substituents on the azacyclic ring may give rise to cis and transdiastereoisomers, of which the cis stereochemistry is preferred. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention.

Certain particularly apt compounds of the present invention includethose wherein R¹ is a group selected from pyrrole, furan, thiene,pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole,isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole,thiadiazole, triazine, and tetrazole, each of which heteroaryl groupsbeing optionally substituted as previously defined.

Preferred compounds of the present invention are those wherein R¹ is agroup selected from furan, pyridine, pyrazole, imidazole, oxazole,isoxazole, pyrazine, pyrimidine, thiazole, 1,2,3-triazole,1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and tetrazole, eachof which heteroaryl groups being optionally substituted as previouslydefined.

Certain particularly apt compounds of the present invention includethose wherein R¹ is a 5-membered aromatic heterocyclic group. Preferredcompounds are those wherein R¹ is a 5-membered aromatic heterocyclicgroup containing 1, 2, 3 or 4 nitrogen atoms, for instance, ##STR3##where R¹⁰ is hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, SR^(x), SOR^(x), SO₂ R^(x), phenyl, NR^(a) R^(b), NR^(a) COR^(x),CH₂ COCF₃ or CF₃, where R^(a) and R^(b) are independently hydrogen orC₁₋₄ alkyl, and R^(x) is C₁₋₄ alkyl.

Particularly preferred compounds of the present invention are thosewherein R¹ is a group selected from ##STR4## where R¹⁰ is as previouslydefined.

An especially preferred class of compound of formula (I) is that whereinR¹ is the group ##STR5## wherein R¹⁰ is as previously defined.

R¹⁰ is preferably hydrogen, C₁₋₄ alkyl (especially methyl), amino, C₁₋₄alkylamino (especially methylamino), di(C₁₋₄ alkyl)amino (especiallydimethylamino or diethylamino), NC(O)C₁₋₄ alkyl (especiallyNC(O)methyl), CH₂ C(O)CF₃ or CF₃.

Most aptly R² is C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, CF₃ or OCF₃.

Favourably R² is C₁₋₄ alkoxy, halogen, CF₃ or OCF₃.

More preferably R² is methoxy, ethoxy, propoxy, isopropoxy, fluorine,chlorine, CF₃ or OCF₃.

Most preferably R² is in the meta- or para-position with respect to thegroup R¹ --(CH₂)_(m) --.

Most preferably R² is methoxy.

Preferably R³ is hydrogen or C₁₋₄ alkyl.

Most preferably, R³ is hydrogen or methyl.

Most aptly R⁴ is hydrogen.

Most aptly R⁵ is hydrogen, fluorine, chlorine or CF₃.

Preferably R⁴ is hydrogen and R⁵ is hydrogen or 4-fluoro.

Suitable values for R^(6a) include hydrogen, methyl and ethyl.

Preferably R^(6a) is hydrogen or methyl, more preferably hydrogen.

Preferably R^(6b) is C₁₋₄ alkyl optionally substituted by a hydroxygroup, such as methyl, ethyl, CH₂ OH, CH₂ CH₂ OH, CH(OH)CH₃ orC(OH)(CH₃)₂, or the group --CO₂ R^(c) where R^(c) is C₁₋₄ alkyl such asC(O)OCH₃ or C(O)OCH₂ CH₃.

More preferably, R^(6b) is methyl or CH₂ OH.

When present, R⁹ is preferably methyl. For the avoidance of doubt, R⁹ isattached to any available carbon atom on the azacyclic ring.

Preferably m is zero.

Preferably n is 2.

Preferably p is zero or 1.

Preferably q is zero.

A particular sub-class of compounds according to the present inventionis represented by compounds of formula (Ia), and pharmaceuticallyacceptable salts and prodrugs thereof: ##STR6## wherein

R¹, R², R³, R^(6b) and p are as defined for formula (I) above; and A¹ isfluorine or hydrogen.

Specific compounds within the scope of the present invention include:

(±)-2,3-cis-N-{1-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethyl}-2-phenylpiperidin-3-amine;

(±)-2,3-cis-2-[(2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanol;

and pharmaceutically acceptable salts and prodrugs thereof.

Further preferred compounds within the scope of the present inventionare described in the Examples described herein.

In a further aspect of the present invention, the compounds of formula(I) will preferably be prepared in the form of a pharmaceuticallyacceptable salt, especially an acid addition salt.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable acid such as hydrochloric acid, fumaricacid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the "parent drug" or "parent molecule")that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

Thus, for example, certain preferred prodrugs may not be antagonists oftachykinin, particularly substance P, activity to any significant extent(or not at all). Such compounds, however, are still advantageous intreating the various conditions described herein, especially where aninjectable formulation is preferred.

The advantages of a prodrug may lie in its physical properties, such asenhanced water solubility for parenteral administration compared withthe parent drug, or it may enhance absorption from the digestive tract,or it may enhance drug stability for long-term storage. Ideally aprodrug will improve the overall efficacy of a parent drug, for example,through the reduction of toxicity and unwanted effects of drugs bycontrolling their absorption, blood levels, metabolism, distribution andcellular uptake.

The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention have at least three asymmetriccentres, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The preferred compounds of the formula (I) and(Ia) will have the 2- and3- substituent cis and the preferred stereochemistry at the 2-positionis 2-(S)- whilst the preferred stereochemistry of the 3-position is3-(S).

Thus for example as shown in formula (Ib) ##STR7##

The present invention further provides pharmaceutical compositionscomprising one or more compounds of formula (I) in association with apharmaceutically acceptable carrier.

Preferably the compositions according to the invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Preferred compositions for administration by injection include thosecomprising a compound of formula (I), as the active ingredient, inassociation with a surface-active agent (or wetting agent or surfactant)or in the form of an emulsion (as a water-in-oil or oil-in-wateremulsion).

Suitable surface-active agents include anionic agents such as sodiumbis-(2-ethylhexyl)sulfosuccinate (docusate sodium), cationic agents,such as alkyltrimethylammonium bromides, (e.g. cetyltrimethylammoniumbromide (cetrimide)), and in particular, non-ionic agents, such aspolyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) and othersorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with asurface-active agent will conveniently comprise between 0.05 and 5%surface-active agent, and preferably between 0.1 and 2.5%. It will beappreciated that other ingredients may be added, for example mannitol orother pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fatemulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ andLipiphysan™. The active ingredient may be either dissolved in apre-mixed emulsion composition or alternatively it may be dissolved inan oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil,corn oil or almond oil) and an emulsion formed upon mixing with aphospholipid (e.g. egg phospholipids, soybean phospholipids or sovbeanlecithin) and water. It will be appreciated that other ingredients maybe added, for example glycerol or glucose, to adjust the tonicity of theemulsion. Suitable emulsions will typically contain up to 20% oil, forexample, between 5 and 20%. The fat emulsion will preferably comprisefat droplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, andhave a pH in the range of 5.5 to 8.0.

Particularly preferred emulsion compositions are those prepared bymixing a compound of formula (I) with Intralipid™ or the componentsthereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The present invention further provides a process for the preparation ofa pharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity.

Thus, for example, an excess of tachykinin, and in particular substanceP, activity is implicated in a variety of disorders of the centralnervous system. Such disorders include mood disorders, such asdepression or more particularly depressive disorders, for example,single episodic or recurrent major depressive disorders and dysthymicdisorders, or bipolar disorders, for example, bipolar I disorder,bipolar II disorder and cyclothymic disorder; anxiety disorders, such aspanic disorder with or without agoraphobia, agoraphobia without historyof panic disorder, specific phobias, for example, specific animalphobias, social phobias, obsessive-compulsive disorder, stress disordersincluding post-traumatic stress disorder and acute stress disorder, andgeneralised anxiety disorders; schizophrenia and other psychoticdisorders, for example, schizophreniform disorders, schizoaffectivedisorders, delusional disorders, brief psychotic disorders, sharedpsychotic disorders and psychotic disorders with delusions orhallucinations; delerium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Alzheimer's disease, seniledementia, dementia of the Alzheimer's type, vascular dementia, and otherdementias, for example, due to HIV disease, head trauma, Parkinson'sdisease, Huntington's disease, Pick's disease, Creutzfeldt-Jakobdisease, or due to multiple aetiologies; Parkinson's disease and otherextra-pyramidal movement disorders such as medication-induced movementdisorders, for example, neuroleptic-induced parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremour; substance-relateddisorders arising from the use of alcohol, amphetamines (oramphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens,inhalants and aerosol propellants, nicotine, opioids, phenylglycidinederivatives. sedatives, hypnotics, and anxiolytics, whichsubstance-related disorders include dependence and abuse, intoxication,withdrawal, intoxication delerium, withdrawal delerium, persistingdementia. psychotic disorders, mood disorders, anxiety disorders, sexualdysfunction and sleep disorders; epilepsy; Down's syndrome;demyelinating diseases such as MS and ALS and other neuropathologicaldisorders such as peripheral neuropathy, for example diabetic andchemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia and other neuralgias; andcerebral vascular disorders due to acute or chronic cerebrovasculardamage such as cerebral infarction, subarachnoid haemorrhage or cerebraloedema.

Tachykinin, and in particular substance P, activity is also involved innociception and pain. The compounds of the present invention willtherefore be of use in the prevention or treatment of diseases andconditions in which pain predominates, including soft tissue andperipheral damage, such as acute trauma, osteoarthritis, rheumatoidarthritis, musculo-skeletal pain, particularly after trauma, spinalpain, dental pain, myofascial pain syndromes, headache, episiotomy pain,and burns; deep and visceral pain, such as heart pain, muscle pain, eyepain, orofacial pain, for example, odontalgia, abdominal pain,gynaecological pain, for example, dysmenorrhoea, and labour pain; painassociated with nerve and root damage, such as pain associated withperipheral nerve disorders, for example, nerve entrapment and brachialplexus avulsions, amputation, peripheral neuropathies, tic douloureux,atypical facial pain, nerve root damage, and arachnoiditis; painassociated with carcinoma, often referred to as cancer pain; centralnervous system pain, such as pain due to spinal cord or brain stemdamage; low back pain; sciatica: ankylosing spondylitis, gout; and scarpain.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of respiratory diseases, particularly thoseassociated with excess mucus secretion, such as chronic obstructiveairways disease, bronchopneumonia, chronic bronchitis, cystic fibrosisand asthma, adult respiratory distress syndrome, and bronchospasm:inflammatory diseases such as inflammatory bowel disease, psoriasis,fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;allergies such as eczema and rhinitis; hypersensitivity disorders suchas poison ivy; ophthalmic diseases such as conjunctivitis, vernalconjunctivitis, and the like; ophthalmic conditions associated with cellproliferation such as proliferative vitreoretinopathy; cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of neoplasms, including breast tumours,neuroganglioblastomas and small cell carcinomas such as small cell lungcancer.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of gastrointestinal (GI) disorders, includinginflammatory disorders and diseases of the GI tract such as gastritis,gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disordersassociated with the neuronal control of viscera, ulcerative colitis,Crohn's disease, irritable bowel syndrome and emesis, including acute,delayed or anticipatory emesis such as emesis induced by chemotherapy,radiation, toxins, viral or bacterial infections, pregnancy, vestibulardisorders, for example, motion sickness, vertigo, dizziness andMeniere's disease, surgery, migraine, variations in intercranialpressure, gastro-oesophageal reflux disease, acid indigestion, overindulgence in food or drink, acid stomach, waterbrash or regurgitation,heartburn, for example, episodic, nocturnal or meal-induced heartburn,and dyspepsia.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of a variety of other conditions including stressrelated somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; adverse immunological reactions such asrejection of transplanted tissues and disorders related to immuneenhancement or suppression such as systemic lupus erythematosus; plasmaextravasation resulting from cytokine chemotherapy, disorders of bladderfunction such as cystitis, bladder detrusor hyper-reflexia andincontinence; fibrosing and collagen diseases such as scleroderma andeosinophilic fascioliasis; disorders of blood flow caused byvasodilation and vasospastic diseases such as angina, vascular headache,migraine and Reynaud's disease; and pain or nociception attributable toor associated with any of the foregoing conditions, especially thetransmission of pain in migraine.

The compounds of formula (I) are also of value in the treatment of acombination of the above conditions, in particular in the treatment ofcombined post-operative pain and post-operative nausea and vomiting.

The compounds of formula (I) are particularly useful in the treatment ofemesis, including acute, delayed or anticipatory emesis, such as emesisinduced by chemotherapy, radiation, toxins, pregnancy, vestibulardisorders, motion, surgery, migraine, and variations in intercranialpressure. Most especially, the compounds of formula (I) are of use inthe treatment of emesis induced by antineoplastic (cytotoxic) agents,including those routinely used in cancer chemotherapy, and emesisinduced by other pharmacological agents, for example, rolipram.

Examples of such chemotherapeutic agents include alkylating agents, forexample, nitrogen mustards, ethyleneimine compounds, alkyl sulphonatesand other compounds with an alkylating action such as nitrosoureas,cisplatin and dacarbazine; antimetabolites, for example, folic acid,purine or pyrimidine antagonists; mitotic inhibitors, for example, vincaalkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.

Particular examples of chemotherapeutic agents are described, forinstance, by D. J. Stewart in Nausea and Vombiting: Recent Research andClinical Advainces, Eds. J. Kucharczyk et al, CRC Press Inc. Boca Raton.Fla., USA (1991) pages 177-203, especially page 188. Commonly usedchemotherapeutic agents include cisplatin, dacarbazine (DTIC),dactinomycin, mechlorethamine (nitrogen mustard). streptozocin.cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin(adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine,etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine,bleomycin and chlorambucil [R. J. Gralla et al in Cancer TreatmentReports (1984) 68(1), 163-172].

The compounds of formula (I) are also of use in the treatment of emesisinduced by radiation including radiation therapy such as in thetreatment of cancer, or radiation sickness; and in the treatment ofpost-operative nausea and vomiting.

It will be appreciated that the compounds of formula (I) may bepresented together with another therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use for the reliefof emesis. Such combined preparations may be, for example, in the formof a twin pack.

A further aspect of the present invention comprises the compounds offormula (I) in combination with a 5-HT₃ antagonist, such as ondansetron,granisetron or tropisetron, or other anti-emetic medicaments, forexample, a dopamine antagonist such as metoclopramide or GABA_(B)receptor agonists such as baclofen. Additionally, a compound of formula(I) may be administered in combination with an anti-inflammatorycorticosteroid, such as dexamethasone, triamcinolone, triamcinoloneacetonide, flunisolide, budesonide, or others such as those disclosed inU.S. Pat. Nos. 2,789,118, 2,990,401, 3,048,581, 3,126.375, 3,929,768,3,996,359, 3,928,326 and 3,749,712. Dexamethasone (Decadron™) isparticularly preferred. Furthermore, a compound of formula (I) may beadministered in combination with a chemotherapeutic agent such as analkylating agent, antimetabolite, mitotic inhibitor or cytotoxicantibiotic, as described above. In general. the currently availabledosage forms of the known therapeutic agents for use in suchcombinations will be suitable.

When tested in the ferret model of cisplatin-induced emesis described byF. D. Tattersall et al, in Eur. J. pharmacol., (1993) 250. R5-R6, thecompounds of the present invention were found to attenuate the retchingand vomiting induced by cisplatin.

The compounds of formula (I) are also particularly useful in thetreatment of pain or nociception and/or inflammation and disordersassociated therewith such as, for example, neuropathy, such as diabeticand chemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis, headache and especiallymigraine.

The present invention further provides a compound of formula (I) for usein therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment of physiological disorders associated withan excess of tachykinins, especially substance P.

The present invention also provides a method for the the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

For the treatment of certain conditions it may be desirable to employ acompound according to the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of formula (I) may beused in conjunction with a bronchodilator, such as a β₂ -adrenergicreceptor agonist or tachykinin antagonist which acts at NK-2 receptors.The compound of formula (I) and the bronchodilator may be administeredto a patient simultaneously, sequentially or in combination.

Likewise, a compound of the present invention may be employed with aleukotriene antagonists, such as a leukotriene D₄ antagonist such as acompound selected from those disclosed in European patent specificationnos. 0 480 717 and 0 604 114 and in U.S. Pat. Nos. 4,859,692 and5,270,324. This combination is particularly useful in the treatment ofrespiratory diseases such as asthma, chronic bronchitis and cough.

The present invention accordingly provides a method for the treatment ofa respiratory disease, such as asthma, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of formula (I) and an effective amount of a bronchodilator.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

It will be appreciated that for the treatment or prevention of migraine,a compound of the present invention may be used in conjunction withother anti-migraine agents, such as ergotamines or 5-HT₁ agonists,specially sumatriptan, naratriptan, zolmatriptan or rizatriptan.

Likewise, for the treatment of behavioural hyperalgesia, a compound ofthe present invention may be used in conjunction with an antagonist ofN-methyl D-aspartate (NMDA), such as dizocilpine.

For the treatment or prevention of inflammatory conditions in the lowerurinary tract, especially cystitis, a compound of the present inventionmay be used in conjunction with an antuinflammatory agent such as abradvkinin receptor antagonist.

It will be appreciated that for the treatment or prevention of pain ornociception, a compound of the present invention may be used inconjunction with other analgesics, such as acetaminophen (paracetamol),aspirin and other NSAIDs and, in particular, opioid analgesics,especially morphine. Specific anti-inflammatory agents includediclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam andsulindac. Suitable opioid analgesics of use in conjunction with acompound of the present invention include morphine, codeine,dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone,levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol,fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxypheneand pentazocine; or a pharmaceutically acceptable salt thereof.Preferred salts of these opioid analgesics include morphine sulphate,morphine hydrochloride, morphine tartrate, codeine phosphate, codeinesulphate, dihydrocodeine bitartrate, diacetylmorphine hydrochloride,hydrocodone bitartrate, hydromorphone hydrochloride, levorphanoltartrate, oxymorphone hydrochloride, alfentanil hydrochloride,buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate,meperidine hydrochloride, methadone hydrochloride, nalbuphinehydrochloride, propoxyphene hydrochloride, propoxyphene napsylate(2-naphthalenesulphonic acid (1:1) monohydrate), and pentazocinehydrochloride.

Therefore, in a further aspect of the present invention, there isprovided a pharmaceutical composition comprising a compound of thepresent invention and an analgesic, together with at least onepharmaceutically acceptable carrier or excipient.

In a further or alternative aspect of the present invention, there isprovided a product comprising a compound of the present invention and ananalgesic as a combined preparation for simultaneous, separate orsequential use in the treatment or prevention of pain or nociception.

It will be appreciated that for the treatment of depression or anxiety,a compound of the present invention may be used in conjunction withother anti-depressant or anti-anxiety agents.

Suitable classes of anti-depressant agent include norepinephrinereuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors(SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists and atypical anti-depressants.

Suitable norepinephrine reuptake inhibitors include tertiary aminetricyclics and secondary amine tricyclics. Suitable examples of tertiaryamine tricyclics include: amitriptyline, clomipramine, doxepin,imipramine and trimipramine, and pharmaceutically acceptable saltsthereof. Suitable examples of secondary amine tricyclics include:amoxapine, desipramine, maprotiline, nortriptyline and protriptyline,and pharmaceutically acceptable salts thereof.

Suitable selective serotonin reuptake inhibitors include: fluoxetine,fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptablesalts thereof.

Suitable monoamine oxidase inhibitors include: isocarboxazid,phenelzine, tranylcypromine and selegiline, and pharmaceuticallyacceptable salts thereof.

Suitable reversible inhibitors of monoamine oxidase include:moclobemide, and pharmaceutically acceptable salts thereof.

Suitable serotonin and noradrenaline reuptake inhibitors of use in thepresent invention include: venlafaxine, and pharmaceutically acceptablesalts thereof.

Suitable CRF antagonists include those compounds described inInternational Patent Specification Nos. WO 94/13643, WO 94/13644, WO94/13661, WO 94/13676 and WO 94/13677.

Suitable atypical anti-depressants include: bupropion, lithium,nefazodone, trazodone and viloxazine, and pharmaceutically acceptablesalts thereof.

Suitable classes of anti-anxiety agent include benzodiazepines and5-HT_(1A) agonists or antagonists, especially 5-HT_(1A) partialagonists, and corticotropin releasing factor (CRF) antagonists.

Suitable benzodiazepines include: alprazolam, chlordiazepoxide,clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam andprazepam, and pharmaceutically acceptable salts thereof.

Suitable 5-HT_(1A) receptor agonists or antagonists include, inparticular, the 5-HT_(1A) receptor partial agonists buspirone,flesinoxan, gepirone and ipsaperone, and pharmaceutically acceptablesalts thereof.

Therefore, in a further aspect of the present invention, there isprovided a pharmaceutical composition comprising a compound of thepresent invention and an anti-depressant or anti-anxiety agent, togetherwith at least one pharmaceutically acceptable carrier or excipient.

In a further or alternative aspect of the present invention, there isprovided a product comprising a compound of the present invention and ananti-depressant or anti-anxiety agent as a combined preparation forsimultaneous, separate or sequential use for the treatment or preventionof depression and/or anxiety.

The excellent pharmacological profile of the compounds of the presentinvention offers the opportunity for their use in therapy at low dosesthereby minimising the risk of unwanted side effects.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day.

For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

In the treatment of emesis using an injectable formulation. a suitabledosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005to 5 mg/kg per day, and especially 0.01 to 2 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

It will be appreciated that the amount of a compound of formula (I)required for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

The compounds according to the present invention may be prepared by aprocess (A) which comprises reacting a compound of formula (II) with acompound of formula (III): ##STR8## wherein R¹, R², R⁴, R⁵, R^(6a),R^(6b), R⁹ m, n, p and q are as defined for formula (I), except that anyreactive moiety is protected by a suitable protecting group; and one ofR³⁰ and R³¹ represents a leaving group and the other of R³⁰ and R³¹represents NHR³, where R³ is as defined for formula (I); in the presenceof a base, followed by deprotection, if required.

Suitably R³⁰ represents NHR³ and R³¹ represents a leaving group.

Suitable leaving groups include halogen atoms, e.g. chlorine, bromine oriodine, or sulphonate derivatives such as tosylate, mesylate ortriflate.

The reaction is conveniently carried out in a suitable organic solvent,such as an ether, e.g. 1,2-dimethoxyethane, at a temperature in theregion of 0° C. Favoured bases of use in the reaction include alkalimetal amides and hydrides, such as potassium bis(trimethylsilyl)amide orpotassium hydride. Suitably, sodium hydride is used.

According to another process (B), compounds of formula (I) whereinR^(6a) iS hydrogen, may be prepared by the reductive amination of acompound of formula (II) in which R³⁰ is the group NHR³, with a compoundof formula (IV), in the presence of a reducing agent: ##STR9##

Suitable reducing agents for use in this reaction include, for example,sodium cyanoborohydride or sodium triacetoxyborohydride, or catalytichydrogenation. The reaction is conveniently effected in a suitablesolvent such as acetic acid or methanol at a temperature between 0° C.and 50° C., conveniently at about room temperature.

According to another general process (C), compounds of formula (I)wherein m is zero and R¹ is a tetrazol-1-yl group substituted by a5-amino moiety may be prepared by reaction of intermediates of formula(V) ##STR10## with ammonium chloride and sodium azide at elevatedtemperature, conveniently in a solvent such as dimethylformamide.

According to another general process (D), compounds of formula (I) maybe prepared by a coupling reaction between a compound of formula (I) and(VII) ##STR11## wherein one of R⁴⁰ and R⁴¹ is B(OH)₂ or Sn(alkyl)₃ or aderivative thereof, and the other is a leaving group such as a halogenatom e.g. bromine or iodine, or --OSO₂ CF₃. Where one of R⁴⁰ and R⁴¹ isB(OH)₂, the reaction is conveniently effected in the presence of apalladium (0) catalyst such as tetrakis(triphenylphosphine)palladium (0)in a suitable solvent such as an ether, for example, dimethoxyethane atan elevated temperature. Where one of R⁴⁰ and R⁴¹ is Sn(alkyl)₃, thereaction is conveniently effected in the presence of palladium (II)catalyst such as bis(triphenylphosphine) palladium (II) chloride, in asuitable solvent such as an aromatic hydrocarbon, for example, toluene,at an elevated temperature.

According to another general process (E), compounds of formula (I) maybe prepared by reduction of a compound of formula (VIII) ##STR12## (withthe proviso that R⁹ is not oxo). Suitable reducing agents will bereadily apparent to one skilled in the art and include, for example,borane or metallic hydrides, such as lithium aluminium hydride or sodiumborohydride. Borane is preferred.

Further details of suitable procedures will be found in the accompanyingExamples.

Compounds of formula (VIII) may be prepared by reductive amination of acompound of formula (IX) ##STR13## wherein any reactive moiety isprotected by a suitable protecting group using, for example, sodiumcyanoborohydride or sodium triacetoxyborohydride and a compound of theformula (III) in which R³¹ is a leaving group such as a halogen atom,for example, a bromine atom. The reaction is effected in the presence ofa base, for example, potassium carbonate and in a suitable solvent suchas dimethylformamide.

It will be appreciated that the product of the reductive aminationmethod described herein will be a mixture of stereoisomers at theposition of the group R^(6a). For the subsequent preparation of aspecific isomer of a compound of formula (I) wherein R^(6a) is hydrogenand R^(6b) is, for example, C₁₋₆ alkyl, the mixture of stereoisomers maybe resolved by conventional methods, for example, by columnchromatography.

Methods for the preparation of intermediates of formula (IX) and formula(II) when R³⁰ is NHR³ are described, for example, in European PatentSpecification No. 0 436 334.

Where they are not commercially available, the intermediates of formulae(III), (IV) and (VII) above may be prepared by procedures which will bereadily apparent to one skilled in the art, for instance, usingmethodology such as that described in International Patent SpecificationNo. WO 95/08549, published Mar. 30th 1995.

Intermediates of formula (VI) may be prepared by method analogous tothose described herein.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers theseisomers may, if desired, be separated, suitably by conventionaltechniques such as preparative chromatography.

The novel compounds may be prepared in racemic form, or individualenantiomers may be prepared either by enantiospecific synthesis or byresolution. For example, compounds which contain a hydroxy group may beresolved into their component enantiomers by standard techniques, suchas the formation of diastereomeric esters or amides, followed bychromatographic separation or separation by fractional crystallizationand removal of the chiral auxiliary. Where they are intermediates,diastereomeric alcohols can then be used to prepare optically purecompounds of formula (I).

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

Tachykinin antagonist activity for compounds of the present inventionmay be demonstrated by the methods set out at pages 36 to 39 ofInternational Patent Specification No. WO 93/01165.

The compounds of this invention may be formulated as specificallyillustrated at pages 35 to 36 of International Patent Specification No.WO 93/01165.

The following Examples illustrate the preparation of compounds accordingto the invention.

EXAMPLE 1(±)-2,3-cis-N-{1-[2-Methoxy-5-(1H-tetrazol-1-yl)phenyl]ethyl}-2-phenylpiperidin-3-aminedihydrochloride

(i) N-(3-Acetyl-4-methoxyphenyl)acetamide

Methyl iodide (3.42 ml, 7.81 g, 55 mmol) was added to a stirred mixtureof N-(3-acetyl-4-hydroxyphenyl)acetamide (J.Org.Chem. 1995, 60,4324-4330) (9.65 g, 50 mmol) and potassium carbonate (13.82 g, 100 mmol)in dimethylformamide (50 ml). The mixture was stirred at roomtemperature for 72 hours, then the solvent was evaporated under reducedpressure. Water (100 ml) was added and the mixture was extracted withethyl acetate (6×100 ml). The combined organic fractions were dried(MgSO₄) and evaporated under reduced pressure to giveN-(3-acetyl-4-methoxyphenyl)acetamide as a tan solid (10.34 g, 100%), ¹H NMR (d₆ -DMSO) δ 9.91 (1H, br. s), 7.76 (2H, m), 7.12 (1H, d, J=9.6Hz), 3.86 (3H, s), 2.52 (3H, s), and 2.01 (3H, s). m/e (CI⁺) 208 (MH⁺).

(ii) 1-(5-Amino-2-methoxyphenyl)ethanone

Hydrochloric acid (6M, 50 ml) was added to a mixture ofN-(3-acetyl-4-methoxyphenyl)acetamide (10.34 g, 50 mmol) and ethanol(150 ml) and the mixture was stirred under reflux for 8 hours. Themixture was cooled and the solvent was evaporated under reducedpressure. Water (100 ml) was added and the pH was adjusted to 10.0 withsaturated aqueous potassium carbonate. The mixture was extracted withdichloromethane (3×100 ml) and the combined organic fractions were dried(MgSO₄) and evaporated under reduced pressure to give1-(5-amino-2-methoxyphenyl)ethanone as a dark oil (8.16 g, 99%), ¹ H NMR(CDCl₃) δ 7.09 (1H, d, J=2.8 Hz), 6.82 (2H, m), 3.84 (3H, s), and 3.34(2H, br. s), 2.59 (3H, s). m/e (CI⁺) 166 (MH⁺).

(iii) 1-[2-Methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanone

Triethyl orthoformate (28.79 ml, 25.65 g, 173 mmol) was added to astirred, heated (80° C.) solution of 1-(5-amino-2-methoxyphenyl)ethanone(8.16 g, 49 mmol) in acetic acid (80 ml) and the mixture was stirred at75° C. for 1 hour. Sodium azide (9.64 g, 148 mmol) was added in portionsover 90 minutes, then the mixture was stirred at 75° C. for 4 hours. Themixture was cooled to room temperature and the solvent was evaporatedunder reduced pressure. Hydrochloric acid (1M, 100 ml) was added and themixture was stirred at room temperature 1 hour. The solid was collected,flushed with toluene (100 ml) and dried in vacuo at room temperature.The residue was recrystallized from ethanol (700 ml) to give1-[2-methoxy-5-(1H-tetrazol-1-y1)phenyl]ethanone as tan coloured needles(7.88 g, 73%), ¹ H NMR (d₆ -DMSO) δ 10.06 (1H, s), 8.06 (2H, m), 7.46(1H, d, J=7.8 Hz), 3.99 (3H, s), and 2.60 (3H, s). m/e (CI⁺) 219 (MH⁺)

(iv)(±)-2,3-cis-N-{1-[2-Methoxy-5-(1H-tetrazol-1-yl)phenyl]ethyl}-2-phenylpiperidin-3-amine

Titanium tetrachloride (1.0 M solution in dichloromethane, 0.3 ml, 0.3mmol) was added dropwise to a stirred, cooled (0° C.) mixture of (2R3R,2S3S)-cis-2-phenylpiperidin-3-amine (106 mg, 0.6 mmol),1-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanone (131 mg, 0.6 mmol) andtriethylamine (0.25 ml, 182 mg, 1.8 mmol) in dichloromethane (10 ml).The mixture was stirred at room temperature for 1 hour, cooled in iceand sodium cyanoborohydride (113 mg, 1.8 mmol) in methanol (2 ml) wasadded. The mixture was stirred at room temperature for 30 minutes, thenhydrochloric acid (1M, 5 ml) was added. The mixture was stirred at roomtemperature for 1 hour, ethyl acetate (40 ml) was added and the mixturewas extracted with hydrochloric acid (1M, 3×20 ml). The combined aqueousfractions were washed with ethyl acetate (2×20 ml), adjusted to pH 9.0with saturated aqueous potassium carbonate and extracted with ethylacetate (3×20 ml). The combined organic fractions were washed withsaturated sodium hydrogen carbonate (20 ml), dried (MgSO₄) andevaporated under reduced pressure to give crude(±)-2,3-cis-N-{1-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethyl}-2-phenylpiperidin-3-amineas a colourless foam (134 mg).

(v)(±)-2,3-cis-N-{1-[2-Methoxy-5-(1H-tetrazol-1-yl)phenyl]ethyl}-1-tert-butoxycarbonyl-2-phenylpiperidin-3-amine

Di-tert-butyldicarbonate (218 mg, 1 mmol) in dichloromethane (2 ml) wasadded to a stirred, cooled (0° C.) solution of crude(±)-2,3-cis-N-{1-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethyl}-2-phenylpiperidin-3-amine (319 mg) indichloromethane (5 ml) and the mixture was stirred at room temperaturefor 16 hours. Saturated aqueous sodium hydrogen carbonate (20 ml) andwater (10 ml) were added and the mixture was extracted withdichloromethane (3×20 ml). The combined organic fractions were dried(MgSO₄) and evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting with ethylacetate/hexane (40:60 increasing to 70:30) to give(±)-2,3-cis-N-{1-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethyl}1-tert-butoxycarbonyl-2-phenylpiperidin-3-amineas a colourless foam (206 mg, 29% from [2R3R,2S3S]-cis-2-phenylpiperidin-3-amine), ¹ H NMR (CDCl₃) δ 9.00, 8.67(total 1H, each s), 7.77-6.94 (8H, m), 5.47, 5.16 (total 1H, each br.m), 4.39 (1H, m), 3.93, 3.85 (total 3H, each s), 3.90 (1H, m), 3.04-2.80(2H, m), and 1.84-1.16 (17H, m).

(vi)(±)-2,3-cis-N-{1-[2-Methoxy-5-(1H-tetrazol-1-yl)phenyl]ethyl}-2-phenylpiperidin-3-aminedihydrochloride

Ethanolic hydrogen chloride (5M, 4 ml) was added to a stirred, cooled(0° C.) solution of(±)-2,3-cis-N-{1-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethyl}-1-tert-butoxycarbonyl-2-phenylpiperidin-3-amine(206 mg, 0.43 mmol) in ethanol (2 ml) and the mixture was stirred atroom temperature for 90 minutes. The solid was collected and dried invacuo at 60° C. to give(±)-2,3-cis-N-{1-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethyl}(2-phenylpiperidin-3-yl)aminedihydrochloride as a colourless solid (176 mg, 90%), mp 241-243° C. ¹ HNMR (d₆ -DMSO)δ 10.60-9.45 (4H, m), 7.92-7.15 (8H, m). 4.77, 4.12 (total1H, each br. s), 3.74, 3.59 (total 3H, each s), 3.71-3.10 (5H, m). and2.38-1.34 (7H, m). m/e (CI) 379 (MH⁺).

Analysis: C₂₁ H₂₆ N₆ O.2HCl.0.3H₂ O requires: C, 55.22; H, 6.18; N,18.07: Found: C, 55.22; H, 6.31; N, 18.40%. HPLC analysis (210 nm)showed this to consist of a 66:34 mixture of diastereoisomers.

EXAMPLE 2 (±)-2,3-cis-Methyl2-[(2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanoatedihydrochloride

(i) 2-[2-Methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoic acid

Selenium dioxide (2.50 g, 22.5 mmol) was added to a suspension of1-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanone (3.27 g, 15 mmol; fromstep (iii) of Example 1) in pyridine (25 ml) and the mixture was stirredat 100° C. for 3 hours. The mixture was filtered, cooled and the solventwas evaporated under reduced pressure. Water (50 ml) and methanol (10ml) were added and the pH was adjusted to 2.0 with hydrochloric acid(conc.). The mixture was extracted with ethyl acetate (4×50 ml) and thecombined organic fractions were washed with hydrochloric acid (2M, 50ml) and brine (50 ml) dried (MgSO₄) and evaporated under reducedpressure to give 2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoicacid as an orange solid (2.11 g, 57%), ¹ H NMR (d₆ -DMSO) δ 10.10 (1H,s), 8.22 (2H, m), 7.54 (1H, d, J=9.6 Hz), and 3.96 (3H, s).

The aqueous layers were combined, treated with hydrochloric acid (conc.,20 ml) and extracted with ethyl acetate (5×20 ml). The combined organicfractions were dried (MgSO₄) and evaporated under reduced pressure togive additional 2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoicacid (1.36 g, 34%).

(ii) Methyl 2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoate

Methyl iodide (1.87 ml, 4.26 g, 30 mmol) was added to a mixture ofsodium hydrogen carbonate (2.52 g, 30 mmol), and2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoic acid (3.37 g,13.6 mmol) in dimethylformamide (120 ml) and the mixture was stirred atroom temperature for 6 hours. The solvent was evaporated under reducedpressure, saturated aqueous sodium hydrogen carbonate (100 ml) and water(50 ml) were added and mixture was extracted with ethyl acetate (4×100ml). The combined organic fractions were washed with saturated aqueoussodium hydrogen carbonate (4×100 ml), dried (MgSO₄) and evaporated underreduced pressure to give methyl2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoate as an orangesolid (3.36 g, 94%), ¹ H NMR (CDCl₃) δ 9.02 (1H, s), 8.11 (1H, d, J=2.8Hz), 8.03 (1H, dd, J=9.0, 2.8 Hz), 7.23 (1H, d, J=9.0 Hz), 3.99 (3H, s),and 3.96 (3H, s).

(iii) (±)-2,3-cis-Methyl2-[(1-tert-butoxycarbonyl-2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-vl)phenyl]ethanoate

Citric acid (1.15 g, 6 mmol) was added to a mixture of (2R3R,2S3S)-cis-2-phenylpiperidin-3-amine (528 mg, 3 mmol), methyl2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoate (786 mg, 3 mmol)and powdered, activated 3 Å molecular sieves (1.5 g) in methanol (25 ml)and the mixture was stirred at room temperature for 18 hours. Sodiumcyanoborohydride (188 mg, 3 mmol) was added and the mixture was stirredat room temperature for 6 hours. Further sodium cyanoborohydride (188mg, 3 mmol) was added and the mixture was stirred at room temperaturefor 24 hours. The mixture was filtered through Celite™, washing withmethanol and dichloromethane, and the solvent was evaporated underreduced pressure. Ethyl acetate (50 ml) was added and the mixture wasextracted with hydrochloric acid (1M, 3×50 ml). The combined aqueousfractions were washed with ethyl acetate (2×50 ml), adjusted to pH 10.0with saturated aqueous potassium carbonate and extracted withdichloromethane (3×50 ml). The combined organic fractions were dried(MgSO₄) and evaporated under reduced pressure. The residue was dissolvedin dichloromethane (5 ml), cooled in ice and di-tert-butyldicarbonate(357 mg, 1.6 mmol) in dichloromethane (5 ml) was added. The mixture wasstirred at room temperature for 22 hours, saturated aqueous sodiumhydrogen carbonate (20 ml) and water (10 ml) were added and the mixturewas extracted with dichloromethane (3×20 ml). The combined organicfractions were dried (MgSO₄) and evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with ethyl acetate/hexane (50:50 increasing to 70:30) to give(±)-2,3-cis-methyl2-[(1-tert-butoxycarbonyl-2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-ethanoate as a colourless foam(415 mg, 26%), ¹ H NMR (CDCl₃) δ 8.77 (1H, s), 7.74-6.94 (8H, m), 5.29(1H, br. s), 4.92 (1H, s), 3.88 (1H, m), 3.81 (3H, s), 3.69 (3H, s),3.11 (1H, m), 2.80 (2H, m), 1.96-1.53 (4H, m), and 1.39 (9H, s). m/e(CI⁺) 523 (MH⁺).

(iv) (±)-2,3-cis-Methyl2-[(2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanoatedihydrochloride

Methanolic hydrogen chloride (4M, 4 ml) was added to a stirred, cooled(0° C.) solution of (±)-2,3-cis-methyl2-[(1-tert-butoxycarbonyl-2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanoate (339 mg, 0.65 mmol) inmethanol (2 ml) and the mixture was stirred at room temperature for 90minutes. The solvent was evaporated under reduced pressure and theresidue was triturated with ethanol (5 ml). The solid was collected anddried in vacuo at 60° C. to give (±)-2,3-cis-methyl2-[(2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanoatedihydrochloride as a colourless solid (239 mg, 74%), mp 197-199° C., ¹ HNMR (d₆ -DMSO) δ 10.07 (1H, s). 9.54 (1H, br. s), 9.12 (1H, br. s), 7.74(1H, dd, J=8.9, 2.7 Hz), 7.62 (1H, d, J=2.7 Hz), 7.34-7.20 (5H, m), 7.12(1H, d, J=8.9 Hz), 4.45 (1H, br. s), 4.17 (1H, s), 3.65 (1H, br. s),3.57 (3H, s), 3.55 (3H, s), 3.32 (2H, m), 3.00 (2H, m), 2.06 (2H, m),1.85 (1H, m), and 1.65 (1H, m). m/e (CI⁺) 423 (MH⁺).

Analysis: C₂₂ H₂₆ N₆ O₃.2HCl.0.5H₂ O requires: C, 52.39; H, 5.79; N,16.66; Found: C, 52.21; H, 5.70; N, 16.32%. HPLC analysis (210 nm)showed this to consist of an 85:15 mixture of diastereoisomers.

EXAMPLE 3(±)-2,3-cis-2-[(2-Phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanoldihydrochloride

(i)(±)-2,3-cis-2-[(1-tert-Butoxycarbonyl-2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanol

Lithium aluminium hydride (0.5M in dimethoxyethane, 3.06 ml, 1.53 mmol)was added dropwise to a stirred, cooled (-40° C.) solution of(±)-2,3-cis-methyl2-[(1-tert-butoxycarbonyl-2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanoate(570 mg, 1.09 mmol; from step (iii) of Example 2) in tetrahydrofuran (15ml) and the mixture was stirred at (-30° C.) for 30 minutes. Methanol (5ml) was added and the mixture was allowed to warm to room temperature.Saturated aqueous sodium hydrogen carbonate (40 ml) and water (20 ml)were added and mixture was extracted with dichloromethane (3×40 ml). Thecombined organic fractions were dried (MgSO₄) and evaporated underreduced pressure. The residue was purified by medium pressure liquidchromatography on silica gel, eluting with ethyl acetate/hexane (70:30increasing to 100:0). The residue was recrystallized from ethylacetate/hexane (50:50, 15 ml) to give(±)-2,3-cis-2-[(1-tert-butoxycarbonyl-2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanol as a colourlesssolid (282 mg, 52%), ¹ H NMR (CDCl₃) δ 8.86 (1H, br.s), 7.60 (2H, m),7.40 (2H, m), 7.22 (3H, m), 6.95 (1H, d, J=8.9 Hz), 5.18 (1H, br.m),4.35 (1H, br.m), 3.87 (2H, m), 3.81 (3H, s), 3.67 (1H, m), 3.43 (1H, m),3.00 (1H, m), 2.85 (1H, m), 2.13 (1H, br.s), 1.96 (2H, m), 1.79 (1H, m),1.60 (1H, m), and 1.32 (9H, s). m/e (CI⁺) 495 (MH⁺).

(ii)(±)-2,3-cis-2-[(2-Phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanoldihydrochloride

Ethanolic hydrogen chloride (5M, 4 ml) was added to a stirred, cooled(0° C.) suspension of(±)-2,3-cis-2-[(1-tert-butoxycarbonyl-2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanol(267 mg, 0.54 mmol) in ethanol (2 ml) and the mixture was stirred atroom temperature for 90 minutes. The solvent was evaporated underreduced pressure and the residue was triturated with ethanol (5 ml). Thesolid was collected and dried it vacuo at room temperature to give(±)-2,3-cis-2-[(2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanoldihydrochloride as a colorless solid (233 mg, 92%), mp 238-240° C., ¹ HNMR (d₆ -DMSO) δ 10.01 (1H, s), 9.86 (1H, br.s), 7.70 (1H, m), 7.58-7.20(6H, m), 7.12 (1H, d, J=9.0 Hz), 4.73 (1H, br.s), 4.00-3.06 (10H, m),3.60 (3H, s), 2.29 (2H, m), 1.94 (1H, m), and 1.78 (1H, m). m/e (CI⁺)395 (MH⁺).

HPLC analysis (210 nm) showed this to consist of a 93:7 mixture ofdiastereoisomers.

What is claimed is:
 1. A compound of formula (I): ##STR14## wherein R¹represents a 5- or 6-membered aromatic heterocyclic group containing 1,2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulphur, whichis optionally substituted by one or two substituents, selected from C₁₋₄alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, SR^(x), SOR^(x), SO₂R^(x), phenyl, NR^(a) R^(b), NR^(a) COR^(x), CH₂ COCF₃ and CF₃, whereR^(a) and R^(b) are independently hydrogen or C₁₋₄ alkyl and R^(x) isC₁₋₄ alkyl;R² represents halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, OCF₃,NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆alkenyl, C₂₋₆ alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, whereR^(a) and R^(b) each independently represent hydrogen or C₁₋₄ alkyl; R³represents hydrogen or C₁₋₆ alkyl; R⁴ represents hydrogen, halogen, C₁₋₆alkyl, C₁₋₆ alkoxy, hydroxy, CF₃, NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a),CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₄ alkylsubstituted by C₁₋₄ alkoxy, where R^(a) and R^(b) each independentlyrepresent hydrogen or C₁₋₄ alkyl; R⁵ represents hydrogen, halogen, C₁₋₆alkyl, C₁₋₆ alkoxy substituted by C₁₋₄ alkoxy or CF₃ ; R^(6a) representshydrogen, methyl or ethyl; R^(6b) represents C₁₋₆ alkyl substituted by ahydroxy group; R⁹ represents halogen, C₁₋₆ alkyl, oxo, CO₂ R^(a) orCONR^(a) R^(b) ; m is zero or 1; n is 2; p is zero, 1 or 2; and q iszero, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.2. A compound as claimed in claim 1 wherein R¹ is a group selected frompyrrole, furan, thiene, pyridine, pyrazole, imidazole, oxazole,isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine,triazole, oxadiazole, thiadiazole, triazine, and tetrazole, each ofwhich heteroaryl groups being optionally substituted as defined inclaim
 1. 3. A compound as claimed in claim 1 wherein R¹ is a 5-memberedaromatic heterocyclic group selected from: ##STR15## where R¹⁰ ishydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl,SR^(x), SOR^(x), SO₂ R^(x), phenyl, NR^(a) R^(b), NR^(a) COR^(x), CH₂COCF₃ or CF₃, where R^(a) and R^(b) are independently hydrogen or C₁₋₄alkyl, and R^(x) is C₁₋₄ alkyl.
 4. A compound as claimed in claim 3wherein R¹ is the group ##STR16## wherein R¹⁰ is as defined in claim 3.5. A compound as claimed in any claim 1 wherein R² is C₁₋₄ alkyl, C₁₋₄alkoxy, halogen, CF₃ or OCF₃.
 6. A compound as claimed in claim 1wherein R² is in the meta- or para-position with respect to the group R¹-(CH₂)_(m) --.
 7. A compound as claimed in claim 1 wherein R³ ishydrogen or C₁₋₄ alkyl.
 8. A compound as claimed in claim 1 wherein R⁴is hydrogen and R⁵ is hydrogen or 4-fluoro.
 9. A compound of formula(Ia): ##STR17## wherein R¹, R², R³, R^(6b) and p are as defined in claim1; andA¹ is fluorine or hydrogen; or a pharmaceutically acceptable saltor prodrug thereof.
 10. A compound selectedfrom:(±)-2,3-cis-N-{1-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethyl}-2-phenylpiperidin-3-amine;(±)-2,3-cis-2-[(2-phenylpiperidin-3-yl)amino]-2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]ethanol;ora pharmaceutically acceptable salt or prodrug thereof.
 11. Apharmaceutical composition comprising a compound as claimed in claim 1in association with a pharmaceutically acceptable carrier or excipient.12. A method for the treatment of a physiological disorder having anexcess of tachykinins, which method comprises administration to apatient in need thereof of a tachykinin reducing amount of a compoundaccording to claim
 1. 13. A method according to claim 12 for thetreatment of pain or inflammation.
 14. A method according to claim 12for the treatment of migraine.
 15. A method according to claim 12 forthe treatment of emesis.
 16. A method according to claim 12 for thetreatment of postherpetic neuralgia.
 17. A process for the preparationof a compound as claimed in claim 1 which comprises:(A) reacting acompound of formula (II) with a compound of formula (III): ##STR18##wherein R¹, R², R⁴, R⁵, R^(6a), R^(6b), R⁹ m, n, p and q are as definedin claim 1, except that any reactive moiety is protected by a suitableprotecting group; and one of R³⁰ and R³¹ represents a leaving group andthe other of R³⁰ and R³¹ represents NHR³, where R³ is as defined inclaim 1; in the presence of a base, followed by deprotection, ifrequired; or (B), where R^(6a) is hydrogen, reductive amination of acompound of formula (II) in which R³⁰ is the group NHR³, with a compoundof formula (IV): ##STR19## in the presence of a reducing agent; or (C),where m is zero and R¹ is a tetrazol-1-yl group substituted by a 5-aminomoiety, reaction of intermediates of formula (V): ##STR20## withammonium chloride and sodium azide at elevated temperature; or (D), acoupling reaction between a compound of formula (VI) and (VII):##STR21## wherein one of R⁴⁰ and R⁴¹ is B(OH)₂ or Sn(alkyl)₃ or aderivative thereof, and the other is a leaving group; or (E), reductionof a compound of formula (VIII): ##STR22## with the proviso that R⁹ isnot oxo; each process being followed, where necessary, by the removal ofany protecting group where present;and when the compound of formula (I)is obtained as a mixture of enantiomers or diastereoisomers, optionallyresolving the mixture to obtain the desired enantiomer; and/or, ifdesired, converting the resulting compound of formula (I) or a saltthereof, into a pharmaceutically acceptable salt or prodrug thereof.